1
SOFT DRUG APPROACH IN CANNABINOIDS
Thesis presented
By
Jimit Girish Raghav
To
The Bouve’ Graduate School of Health Sciences
In Partial Fulfilment of the Requirements for the Degree of Master of Science
In Pharmaceutical Sciences with specialization in Pharmacology
NORTHEASTERN UNIVERSITY
BOSTON, MASSACHUSETTS
14th, August, 2014
2
Northeastern University
Bouve College of Health Sciences
Thesis Approval
Thesis Title: Soft drug approach in cannabinoids.
Author: Jimit Girish Raghav.
Program: Pharmacology.
Approval for thesis requirements for the Master of Science degree in: Pharmacology
Thesis Committee (Chairman): Dr. Torbjorn Jarbe Date: 08/ 14/2014.
Other Committee members
Dr. David Janero Date: 08/14 /2014.
Dr. Rajeev Desai Date: 08/14 /2014.
Dean of the Bouve College of Health Sciences:
Dr. Tom Olson DATE: .
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4 Table of Contents
Page
List of figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
ACKNOWLEDGEMENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
ABSTARCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
i. STATEMENT OF THE PROBLEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ii. BACKGROUND AND SIGNIFICANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
MATERIALS AND METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
SUMMARY AND DISCUSSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
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List of figures:
Figure1: Chemical structures of all the drugs used in the project . . . . . . . . . 8
Figure 2: Classification of drugs used in this project . . . . . . . . . . . . . . . . . . . . . 8
Figure 3: Overview of metabolic pathway of drugs used in this project . . . . . . 9
Figure 4: Overview of tail-flick latency analgesia assay . . . . . . . . . . . . . . . . . . . . 13, 14
Figure 5 a& b: Tail-flick latency data for drug AM7410 and (-) - ∆8- THC DMH. 14, 15
Figure 6: Tail-flick latency data for drug AM7438 and AM7410 . . . . . . . . . . . . . 16
Figure 7: Dose response curve for drug AM7438 . . . . . . . . . . . . . . . . . . . . . . . . . . 17
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ACKNOWLEDGEMENTS
I would like to take this opportunity and thanks Dr Torbjorn Jarbe, who is my PI and the advisor for the current
thesis. Without your vital support and belief I would have never been able to complete this project. I also express
my deepest gratitude to Dr. David Janero and Dr. Rajeev Desai for being on my committee, your crucial
suggestions, corrections and comments on my project were invaluable. I would also like to offer special thanks to
Dr. Alexandros Makriyannis for his indispensable support he gave me on all my projects here at CDD. I will also
like to appreciate Dr. Spiros Nikas for providing me with all the test molecules without any hesitation for this
project. I would also like to thanks Dr. Kiran Vemuri for guiding me on my research. Last but not least I will like to
thanks Roger Gifford my colleague/supervisor in lab who trained me initially on all the assays and helped me
acclimatized with the lab environment. My heartfelt to thanks my parents; it was their support and nurture
which made me help accomplishing everything in life. A special appreciation to National Institute of Drug Abuse
(NIDA) for providing all the monetary requirements via grants to support all the research done in this project.
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Abstract: The only plant-derived cannabinoid (phytocannabinoid) agent currently used for medical purposes in
the USA is (-) - ∆9- tetrahydrocannabinol (THC). Here, I report the analgesic effects of two novel synthetic
cannabinergic agents, AM7410 and AM7438 which are designed to be “soft-drugs”. Both drugs have
metabolically labile ester groups strategically placed in their chemical structure. This ester group makes AM7410
and AM7438 susceptible to degradation to inactive metabolites by plasma esterases. Both compounds profiled in
this thesis are analogues of (-) - ∆8- THC DMH (AM 10808; DMH = dimethylheptyl). The in vivo data demonstrate
that both AM7410 and AM7438 produce maximal analgesia (1 mg/kg) in a tail-flick withdrawal assay. Both AM
7410 and AM7438 (0.3 mg/kg and 1 mg/kg) showed quick onset and offset of action when compared to (-) - ∆8 -
THC DMH (0.3mg/kg and 1mg.kg). Additionally, data also suggest that the effects induced by AM 7438 (0.3 mg/kg
and 1 mg/kg) have a faster offset when compared to AM7410 (0.3 mg/kg and 1 mg/kg) in the tail-flick assay.
Introduction:
A: Statement of Problem: The aim of this thesis is to evaluate the concept of the “soft-drug” approach in the
field of cannabinoid chemistry/synthesis. The “soft-drug” approach has not yet been extensively analysed in the
cannabinoid field whereas it is a well-established concept in other medicinal chemistry fields such as opioids and
anti-hypertensives.1 A compound is considered to be a “soft drug” if the compound is an analogue of an parent
compound and the analogue has a more predictable and controlled metabolism compared to its parent
compound. A compound can also be labelled as a “soft drug” if the given compound has minimal side effects
when compared with its parent compound.2 In the former case, the analog is synthesised to be a soft drug by
introducing a certain chemical group or certain chemical modification into the structure of the analog which will
make the drug more susceptible to metabolic degradation by enzyme(s).2 One of the most common chemical
modifications employed to generate a soft drug is the introduction of an ester moiety into the parent compound
in an attempt to make the parent compound susceptible to enzymatic inactivation by (plasma) esterases. The
work carried out and presented in this thesis will focus on exploring the above concept for two cannabimimetic
agents. In this current paper the concept of “depot effect” will be discussed along with the concept of “soft-
drug”. The depot effect is typically observed with lipophilic drugs. Drugs with high lipophilicity tend to sequester
into fat tissue before flowing into the systemic circulation and to produce their pharmacological effect. The
8 “depot effect” mainly depends on the log P and topological polar surface area (tPSA) values of the molecules.
Both logP and tPSA are indices of a drug’s lipophilicity and its cell membrane permeability.3 The higher the logP
value of a compound, the higher the lipophilicity. The higher the lipophilicity, the higher the chances that the
compound will get distributed into fat tissues and hence the more likely is the compound’s ability to produce the
depot effect.3 If one is to follow the Lipinski’s rule of five which is set of rules that determines the ability of a test
compound to be used as orally available drug for future consumption by humans.4 According to this rule, the
logP of the compound should be 5 or less to avoid the distribution or sequestration into fat tissues and qualify as
a lead compound for potential human consumption.4
By introducing an ester group in the structures of AM7410 and AM7438 (Fig 1) the polarity (clogP values for
AM7410 and AM7438 are 6.59 and 5.0, respectively) was markedly increased for these two chemical molecules as
compared to their parent analogue i.e. (-) - ∆8 - THC DMH (clogP=9.1). This enhanced polarity would be expected
to reduce the depot effect relative to the more lipophilic parent compound (Fig. 2). A more controlled
deactivation of both AM7410 and AM7438 compared to the parent compound ((-) - ∆8 - THC DMH) will be
achieved by plasma esterases which will lead to the production of inactive metabolites (Fig 3).
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Fig 1: Chemical structures of the three compounds used in this study.
Fig 2: (-) - ∆8 - THC DMH can be categorized here as type B drugs, which are highly lipophilic, and these types of
drugs carry a longer depot effect and are very slowly degraded by plasma esterases. AM7410 and AM7438 would
fall in the type A drug category, as these drugs are more polar and carry less depot effect because of increased
polarity and are quickly hydrolysed by plasma esterases. (Reproduced from Sharma et.al.)5
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Fig 3: The ester introduced in the design of cannabinoids makes this class of novel cannabinoids susceptible to
plasma esterases which convert these molecules into inactive acid metabolites. (Reproduced from Sharma et.al.)5
B: Background and Significance: Research concerning medical uses of marijuana and extracts thereof has
increased considerably over the last several decades. The legalization of marijuana for recreational use in two
states of the USA (Colorado and Washington) has further intensified the need to examine cannabinoid agents
both for their potential therapeutic as well as harmful properties.6 Cannabis sativa is the plant from which active
components of marijuana are extracted. The plant has been used in traditional medicines for several centuries
for conditions such as appetite stimulation, pain management and spasms. 7
The identification of cannabinoid receptors and endogenous cannabinoid-like ligands further helped our
understanding of the pharmacological working(s) of THC as well as other cannabimimetic agents. Two principal
cannabinoid receptors have been identified and named cannabinoid receptor 1 (CB1R), originally characterized by
Devane et al. in 1988,8 and cannabinoid receptor 2 (CB2R), originally described by Munro et.al. in 1991.9 CB1R is
primarily distributed in the CNS and likely is responsible for the major psychotropic activities of THC and other
cannabimimetic agents. CB2R is primarily concentrated in the periphery and especially on immune cells like
macrophages.10 Following these discoveries, two principal endogenous cannabinoid ligands were identified,
namely anandamide (AEA; arachidonoyl ethanolamide) and 2-arachidonoyl glycerol (2-AG).10 2-AG is found in
much higher concentrations in the brain as compared to anandamide, and thus it has been proposed that 2-AG is
the major neurotransmitter molecule in the endocannabinoid signalling system.10
Therapeutic areas: THC is mainly responsible for the psychotropic effects (“high”) of the cannabis plant. Some
therapeutic effects of the cannabis plant are contributed by another cannabinoid constituent in the plant,
cannabidiol (CBD). CBD may act as an anti-emetic, neuroprotective and anti-inflammatory agent.11 There are
11 very few prescription-based cannabinoid preparations available for medical use. Depending on the country,
cannabinoid preparations available in pharmacies are: 1) oral THC marketed as Dronabinol (Marinol®); 2)
Nabilone (brand name: Cisamet), a hexahydrocannabinol structurally related to THC and 3) Nabiximols (Sativex®),
which is marketed as a sublingual spray and contains THC and CBD in a 1:1 ratio.12,13
In the 1970’s and 80’s, several clinical trials were performed to test the efficacy of dronabinol for inhibition of
nausea and vomiting, side effects caused by chemotherapeutic agents.14 The results of the clinical trials
established that oral THC is effective as an anti-emetic to inhibit nausea and vomiting.14 With further studies, it
was found that twice-a-day dosing of 2.5 mg dronabinol results in an effective anti-emetic effect in cancer
patients.14 The orexigenic effect (increased appetite) induced by THC has been known for centuries, and this
effect of THC has been utilized for treating loss of appetite in patients suffering from HIV/AIDS. 15 In recent
decades, clinical trials have suggested efficiency of dronabinol for also treating anorexia.16 Dronabinol has also
been prescribed for the treatment of chronic neuropathic pain, eliciting analgesia in patients suffering from, e.g.,
multiple sclerosis.17 THC can be beneficial to HIV-infected people in treating their neuropathic pain sensations.18
Other small-scale studies have indicated that THC potentially can be used in various chronic pain-related diseases
like rheumatism and fibromyalgia.17
Pharmacokinetic issues with cannabinoids: THC is highly lipophilic and hence, in practical terms, not water
soluble. Its partition coefficient in n-octanol/water is around 6000, which is an experimentally calculated ratio
using a flask shake method.18 THC is also thermo- and photolabile. The pKa value for THC is about 10.6, and the
compound rapidly degrades in an acidic environment.18 For recreational purposes, the most common route of
THC administration is through smoking marijuana. For therapeutic purposes, THC is given by the oral route
(Dronabinol). When given orally, THC absorption is highly erratic and slow.18 Peak plasma concentration may
occur anytime between 60 min to 6 h after ingestion in different subjects. THC is rapidly degraded in the
stomach’s acidic environment. In the stomach, THC is converted into various substituted cannabidiol-like-
products as well as the minor ∆8-THC isomer. THC is also subject to an extensive first-pass metabolism, especially
when given orally. A dronabinol capsule of 10 mg resulted in the bioavailability of only 6 to 7 % THC in the
studied subjects, concomitant with high inter-subject variability.18
12 THC distribution in the body is also one of the issues with oral THC and smoked cannabis. Studies with
radiolabelled THC showed that after chronic THC administration, maximal concentration of THC is found in fat
tissues, and the concentration ratio of THC in fat tissues to brain was 27:1 after 7 days of administration and 64:1
after 27 days of administration.19 It has also been reported that only 1% of total administered THC is required for
its psychoactive effects.19
Given its high lipophilicity, THC rapidly partitions into tissues which are highly perfused, especially adipose tissues.
This sequestration of THC in fat tissue accounts for its appreciable volume of distribution along with a very slow
elimination rate and, especially in the case of oral ingestion, delayed pharmacological effects resulting from the
depot effect.19 The depot effect seen with THC may be attributed to the direct deposition of THC in adipose
tissues or, as several studies reported, THC’s active metabolite, namely 11-OH-THC. 11-OH THC forms conjugates
with fatty acid in adipose tissues. It is still unclear whether the depot effect seen with THC is because of THC itself
or because of the reactivity of11-0H THC with fatty acids in adipose tissues. Haggerty et.al20 reported that 11-OH
THC forms a conjugate with palmitic acid, and the resulting conjugate, 11-palmitoyl –delta-9-THC, is a psycho-
active compound in that it produces catalepsy (muscle rigidity) and hypothermia (lowered temperature) when
injected to rats.
Effect of THC in laboratory animals: In parallel with humans, laboratory animals also experience behavioural and
physiological effects of THC (e.g., catalepsy and hypothermia). Since the early 1980’s, the tetrad test has been
employed to evaluate the effects of novel cannabinoid agents.21 The tetrad test includes four characteristic
behaviours induced by cannabimimetic agents in laboratory animals: 1- decrease in spontaneous activity, or hypo
locomotion; 2- analgesia; 3- catalepsy; and 4- hypothermia.22 This tetrad test was developed primarily for
rodents. Mice display more profound hypothermia and analgesia compared to rats, which prompted me to use
mice in the reported studies.22 The analgesia test component was selected over other tetrad tests based on my
preliminary studies, which suggested that analgesia induced by cannabinoid agents and evaluated in the standard
tail-flick test parallels the proposed “soft-drug” profile of the drugs. Tail-flick latency increases with an increase in
drug level in the body, and latency decreases as the tested drug level deceases in body as it gets metabolized to
its respective inactive metabolite. Tail-flick withdrawal in a hot water bath was selected over other analgesia
assays because of its ease and efficiency.
13 The validity of the soft drug approach has already been demonstrated with drugs like esmolol (a class II anti-
arrhythmic β-blocker) and remifentanil (a potent opioid used during pre and post-operative analgesic), both of
which are now available as prescription medicines. Given the rise of interest of cannabinoids in the field of
medicine (especially as potential pain medications), it will be extremely helpful to examine cannabinoid agonists
designed to be potential soft drugs.
MATERIALS AND METHODS:
Animals: Young (aged 3-4 weeks) male CD-1 mice weighing between 25-35 grams were used. . Mice were
housed in groups of 4 in a single cage. Mice were kept in a 12-hour day, 12-hour night light cycle routine. All the
experiments were performed during the 12-hour light phase. All animals had free access to food and water. Mice
habituated to the new environment of the animal facility for at least one week before any handling or
experiments were performed. For each set of experiments, an experimentally naïve group of mice was used. All
the animals were purchased from a listed Northeastern University approved vendor (Charles River Breeding
Laboratories, Wilmington, MA, USA). All experiments performed were in accordance to the protocol no: 13-1134
R approved by Northeastern University’s Institutional Animal Care and Use Committee (NU-IACUC).
Drugs: AM7410, AM7438 and (-) - ∆8 - THC DMH were provided by the chemistry section of the Center for Drug
Discovery, Northeastern University, Boston, MA. All drugs were stored at -20˚C. For preparing the drug
suspensions, aliquots of thawed drug stock solutions were taken based upon dosing need. Total injection volume
delivered to each mouse was 10 ml/kg. The organics used to prepare injectable forms of all three drugs were
dimethyl sulfoxide (DMSO); Tween 80 and propylene glycol (PEG), in a final concentration of 2%, 4%, and 4%,
respectively, in saline.
Analgesia: A standard mouse tail-flick assay was used to profile the in vivo analgesic effect of the test
compounds. An effective analgesic agent increases the latency time before the animal withdraws its tail from a
warm-water bath. A cartoon representation of the experimental set-up is shown below (Fig 4). Three compounds
(-) - ∆8 - THC DMH, AM7410 and AM7438 were tested in the tail-flick assay at different doses. For each dose,
naïve mice (n=6) were used. Animals experienced 3 days of habituation followed by a testing session (day 4).
This assay was carried out at ambient room temperature (22-24°C). On any given day of testing or habituation
training, animals were acclimatized to the experimental room for 30 min prior to any handling. This
training condition included dipping the terminal 2
the third day, each animal received a saline injection to acclimatize
the test day, the water bath was increased and
min (the baseline reading). A cut-off period of 10 sec was
water. After 30 sec post-recording of the base
predetermined dose. Subsequent readings were recorded
injection. Along with the drug injections, one group (n=6) of mice was kept
this group only received the vehicle instead of drug.
which was timed in seconds and then converted into a Maximum Possible Effect (MPE) score. The formula for
converting raw analgesia data into a MPE score is:
% Maximum Possible Effect (MPE) = 100 * [(Test Response
Response)]
The MPE data are used to generate a dose
potencies, duration of action, onset and offset
acclimatized to the experimental room for 30 min prior to any handling. This
dipping the terminal 2-3 cm of tail in a water bath maintained at 38
a saline injection to acclimatize the animals to the injection procedure. On
creased and maintained at 52°C, and the first reading was taken and noted at
off period of 10 sec was used to prevent any injury to the tail because of the hot
recording of the baseline readings, each animal received the drug injection of
ubsequent readings were recorded at 20 min, 60 min, 180 min, and 360 min post
ns, one group (n=6) of mice was kept reserved for obtaining con
the vehicle instead of drug. The raw data included tail flick withdrawal by each mouse
converted into a Maximum Possible Effect (MPE) score. The formula for
MPE score is:
= 100 * [(Test Response- Baseline Response)/(Maximum Response
used to generate a dose-response curve for each of the three test compounds, from which
potencies, duration of action, onset and offset of action will be determined.
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acclimatized to the experimental room for 30 min prior to any handling. This acclimation
tained at 38˚C for 10 sec. On
the injection procedure. On
52°C, and the first reading was taken and noted at 0
used to prevent any injury to the tail because of the hot
d the drug injection of a
at 20 min, 60 min, 180 min, and 360 min post-drug
ed for obtaining control data;
The raw data included tail flick withdrawal by each mouse,
converted into a Maximum Possible Effect (MPE) score. The formula for
Baseline Response)/(Maximum Response-Baseline
response curve for each of the three test compounds, from which
15 Fig 4: Brief overview the tail-flick analgesia experiment. Only 2 to 3 cm of the distal end of the tail will be dipped
into the water bath.
Statistical Analysis: Statistical comparison of tail-flick latency data obtained from AM410 and (-) - ∆8 - THC DMH
studies will use two-way repeated measures ANOVA along with Bonferroni’s post-hoc test to assess the time-and
dose effect functions. The statistical analysis was performed using GraphPad Prism 5.03 (GraphPad Software, San
Diego, CA). To analyse and compare tail-flick latencies data from AM7438 and AM7410, a linear mixed model
repeated measures ANOVA (IBM® software package, SPSS, v.21) was applied.
RESULTS:
Analgesic effect of AM7410 and (-) - ∆8 - THC DMH: Tail-flick latency data experiments conducted in mice
demonstrated that AM7410 significantly differs from (-) - ∆-8 - THC DMH in terms of its duration of action. It is
evident from Fig. 5 that AM7410 has a quicker onset and quicker offset of action when compared to (-) - ∆8 - THC
DMH. The ANOVA analysis of the tail-flick data showed significant effects for dose (D) [F (2,120)=160.6; P<0.0001]
and time (T) [F(14,120)=4.5; P<0.0001] along with the D × T interaction for three doses (0.1,0.3, 1.0 mg/kg) of each
compound, i.e., AM7410 and (-) - ∆8 - THC DMH. .
5a 5b
Fig. 5 a&b: Tail-flick latencies of mice (n=6 for each dose) in a hot water bath (52˚C) post administration of
AM7410, an ester analog of (-) - ∆8 - THC DMH are shown in Fig. 5a. Tail-flick latencies of mice (n=6) administered
Time (min)
20 60 180 360
% M
PE
0
20
40
60
80
100
Time (min)
20 60 180 360
% M
PE
0
20
40
60
80
100
0.1 mg/kg0.3 mg/kg1.0 mg/kgVehicle
∆∆∆∆8-THC-DMH
AM7410
16 a lower dose (0.1mg/kg) of AM7410, (-) - ∆8 - THC DMH respectively and vehicle are shown in Fig 5b. Latencies
were converted into maximum possible effect (%MPE) displayed on the ordinate. MPE is expressed as the group
mean ±SEM.
Analgesic effect of AM7438: The chemical difference between AM7438 and AM7410 is slight, i.e., AM7438 (log
P=5) contains a cyano group (Fig. 2), which makes the compound more polar vs. AM7410 (log P= 6.59). The tail-
flick latency data is congruent with this difference (Fig. 6). AM 7438 has a shorter duration of action when
compared to AM7410 at the two doses (0.3 mg/kg and 1 mg/kg) examined. A mixed repeated measures ANOVA
applied to the tail-flick latency data with AM 7410 and AM7438 during 180-min and 360-min time points (offset
phase) revealed significant effects for drug (D) [F1,44=8.98; p<0.0004], dose level (L) [F1,44=40.95;p<0.001] and time
(T) [F1,44=28.46;p<0.001]. All the three parameters (D, L, and T) had significant differences when compared pair-
wise using Sidak multiple comparison t-test (p=0.005). This pair-wise comparison of three parameters provides
evidence of a faster off-set of AM7438 as compared to AM7410.
In both the experiments, tail-flick latency caused by vehicle is not compared using statistical analysis graphically
because MPE did not exceed 20% in any of the examined four time-points.
17
Fig 6: Tail-flick latencies of mice (n=6 for each dose) in a hot water bath (52˚C) post administration of AM7438
and AM7410. Latencies are displayed as maximum possible effect (%MPE) and shown on the ordinate. %MPE is
expressed as the group mean ±SEM. The data for AM7410 is reproduced from Fig. 5.
The results generated from testing two lower doses of AM7438 are displayed in Fig.7. A two-way repeated
measures ANOVA indicated significance for Dose (D) [F3, 20 = 125.1], Time (T) [F3, 60 = 61.4] and the interaction
D x T [F9, 60 = 10.8].
Time (min)
20 60 180 360
%M
PE
0
20
40
60
80
100
0.3 mg/kg AM74381.0 mg/kg AM74380.3 mg/kg AM74101.0 mg/kg AM7410
Fig 7: Tail-flick latencies of mice (n=6 for each dose)
of AM7438. Latencies are displayed as maximum possible effect (%MPE)
expressed as the group mean ±SEM.
Summary and Discussion: The main aim of this thesis project was to evaluate the
potential cannabimimetic agents using an in
the analgesic effect in this mouse tail-flick model
pharmacological effect of each test agent.
Results from the tail-flick analgesia studies suggest that both of the novel agent
from their parent analogue (-) - ∆8 - THC DMH
AM7438 both have quicker onsets and offset
polar molecule of the three compounds evaluated
the compound more polar in comparison with AM7410 and
as displayed in Fig6. This increase in polarity
when compared to AM7410. Future studies with these two molecules will involve screening them
vivo and behavioural models to extend the characterization of
example, hypothermia studies with AM7410 and AM7438 along with the presence of a CB1R antagonist will be
of mice (n=6 for each dose) in a hot water bath (52˚C) post administration of four doses
maximum possible effect (%MPE) and shown on the ordinate. %MPE is
The main aim of this thesis project was to evaluate the analgesic effect
cannabimimetic agents using an in-vivo mouse model i.e. tail-flick latency assay. As a function of time,
flick model can be used as a surrogate indicator for the
t agent.
flick analgesia studies suggest that both of the novel agents AM7410 andAM7438
THC DMH in terms of their analgesic time course profile.
and offsets of action as compared to (-) - ∆8 - THC DMH. AM7438 is the mo
evaluated in this study. The cyano group in the AM7438
the compound more polar in comparison with AM7410 and (-) - ∆8 - THC DMH, as observed from clogP values and
his increase in polarity is a likely determinant of the reduced duration of action of AM7438
Future studies with these two molecules will involve screening them
extend the characterization of these two compounds as “soft drugs”.
studies with AM7410 and AM7438 along with the presence of a CB1R antagonist will be
18
˚C) post administration of four doses
on the ordinate. %MPE is
analgesic effect of two novel
As a function of time,
can be used as a surrogate indicator for the time course of the
s AM7410 andAM7438 differs
. Thus, AM7410 and
. AM7438 is the most
in this study. The cyano group in the AM7438 (Fig. 3) makes
as observed from clogP values and
duration of action of AM7438
Future studies with these two molecules will involve screening them using other in-
these two compounds as “soft drugs”. As a specific
studies with AM7410 and AM7438 along with the presence of a CB1R antagonist will be
19 helpful for characterizing the involvement of CB1R in the analgesic effect of these agents. It will also be a
significant step in the development of this project to evaluate these molecules in drug-discrimination models. If
the cannabinoid esters were found substitute for THC in drug discrimination, the esters might represent
potentially safer alternative analgesics with less risk of THC-induced psychobehavioral adverse events for
potential use as pre and post-operative analgesics and pain management in e.g. multiple sclerosis.
References:
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Reviews. Dec.1999, Volume 20, Issue1, pp.58-101.
2- Bodor, N; Buchwald, P. Designing Safer (Soft) Drugs by Avoiding the Formation of Toxic and Oxidative
Metabolites, Molecular Biotechnology. Feb.2004, Volume 26, Issue2, pp.123-132.
3- Ertl, P; Rohde, B; Selzer,P. Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based
Contributions and Its Application to the Prediction of Drug Transport Properties, 2000, Journal of
Medicinal Chemistry, Volume43, pp.3714-3717.
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estimate solubility and permeability in drug discovery and development settings. Mar. 2001, Advanced
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